8-99861802-G-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_152564.5(VPS13B):c.11071G>A(p.Ala3691Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00549 in 1,597,778 control chromosomes in the GnomAD database, including 39 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0031 ( 3 hom., cov: 32)

Exomes 𝑓: 0.0057 ( 36 hom. )

Consequence

VPS13B
NM_152564.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:17

Conservation

PhyloP100: 9.20

Publications

14 publications found

Variant links:

Genes affected

VPS13B (HGNC:2183): (vacuolar protein sorting 13 homolog B) This gene encodes a potential transmembrane protein that may function in vesicle-mediated transport and sorting of proteins within the cell. This protein may play a role in the development and the function of the eye, hematological system, and central nervous system. Mutations in this gene have been associated with Cohen syndrome. Multiple splice variants encoding distinct isoforms have been identified for this gene. [provided by RefSeq, Jul 2008]

VPS13B Gene-Disease associations (from GenCC):

Cohen syndrome
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Myriad Women’s Health, Laboratory for Molecular Medicine, Orphanet, Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp

VPS13B links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.037311763).

BP6

Variant 8-99861802-G-A is Benign according to our data. Variant chr8-99861802-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 95826.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00307 (468/152264) while in subpopulation NFE AF = 0.00548 (373/68016). AF 95% confidence interval is 0.00502. There are 3 homozygotes in GnomAd4. There are 209 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 3 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_152564.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VPS13B	NM_017890.5	MANE Plus Clinical	c.11146G>A	p.Ala3716Thr	missense	Exon 58 of 62	NP_060360.3
	VPS13B	NM_152564.5	MANE Select	c.11071G>A	p.Ala3691Thr	missense	Exon 58 of 62	NP_689777.3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
VPS13B	ENST00000358544.7	TSL:1 MANE Plus Clinical	c.11146G>A	p.Ala3716Thr	missense	Exon 58 of 62	ENSP00000351346.2	Q7Z7G8-1
VPS13B	ENST00000357162.7	TSL:1 MANE Select	c.11071G>A	p.Ala3691Thr	missense	Exon 58 of 62	ENSP00000349685.2	Q7Z7G8-2
VPS13B	ENST00000682153.1		n.*240G>A		non_coding_transcript_exon	Exon 59 of 62	ENSP00000507923.1	A0A804HKG9

Frequencies

GnomAD3 genomes

AF:

0.00308

AC:

469

AN:

152146

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00113

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00282

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000415

Gnomad FIN

AF:

0.0000942

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00550

Gnomad OTH

AF:

0.000956

GnomAD2 exomes

AF:

0.00246

AC:

547

AN:

221998

AF XY:

0.00264

show subpopulations

Gnomad AFR exome

AF:

0.00125

Gnomad AMR exome

AF:

0.00153

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000529

Gnomad NFE exome

AF:

0.00448

Gnomad OTH exome

AF:

0.00253

GnomAD4 exome

AF:

0.00574

AC:

8298

AN:

1445514

Hom.:

Cov.:

AF XY:

0.00555

AC XY:

3977

AN XY:

717176

show subpopulations

African (AFR)

AF:

0.00132

AC:

AN:

33298

American (AMR)

AF:

0.00159

AC:

AN:

42134

Ashkenazi Jewish (ASJ)

AF:

0.000156

AC:

AN:

25706

East Asian (EAS)

AF:

0.00

AC:

AN:

39172

South Asian (SAS)

AF:

0.000878

AC:

AN:

83178

European-Finnish (FIN)

AF:

0.0000959

AC:

AN:

52118

Middle Eastern (MID)

AF:

0.000695

AC:

AN:

5758

European-Non Finnish (NFE)

AF:

0.00703

AC:

7768

AN:

1104332

Other (OTH)

AF:

0.00557

AC:

333

AN:

59818

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.469

Heterozygous variant carriers

566

1133

1699

2266

2832

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

314

628

942

1256

1570

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00307

AC:

468

AN:

152264

Hom.:

Cov.:

AF XY:

0.00281

AC XY:

209

AN XY:

74448

show subpopulations

African (AFR)

AF:

0.00113

AC:

AN:

41558

American (AMR)

AF:

0.00281

AC:

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.000415

AC:

AN:

4816

European-Finnish (FIN)

AF:

0.0000942

AC:

AN:

10612

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00548

AC:

373

AN:

68016

Other (OTH)

AF:

0.000946

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

112

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00411

Hom.:

Bravo

AF:

0.00346

TwinsUK

AF:

0.00701

AC:

ALSPAC

AF:

0.00571

AC:

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.00558

AC:

ExAC

AF:

0.00196

AC:

237

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (8)

Cohen syndrome (3)

not specified (3)

Inborn genetic diseases (1)

Intellectual disability (1)

VPS13B-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.84

BayesDel_addAF

Benign

-0.10

BayesDel_noAF

Uncertain

0.080

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.41

Eigen

Pathogenic

0.70

Eigen_PC

Pathogenic

0.75

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.95

M_CAP

Uncertain

0.11

MetaRNN

Benign

0.037

MetaSVM

Benign

-0.51

MutationAssessor

Benign

1.3

PhyloP100

9.2

PrimateAI

Pathogenic

0.90

PROVEAN

Uncertain

-3.3

REVEL

Uncertain

0.50

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.90

MVP

0.73

MPC

0.30

ClinPred

0.038

GERP RS

5.7

Varity_R

0.72

gMVP

0.93

Mutation Taster

=73/27

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over